Evidence suggests that for the most part gp4l neutralizing epitopes are cryptic, and this is most likely related to the functional role of the transmembrane protein (TM) in mediating virus entry. It has been shown that gpl2O-CD4 binding causes the HIV envelope to undergo a series of conformational changes, which may be driven by the formation of a series of structural intermediates within gp41, leading ultimately to virus entry. Previous work in the applicant's laboratory has identified two regions within the ectodomain of gp4l which play critical roles in this process and recently a crystal structure has been reported for the structure formed by the specific interaction of these two domains. This work supports the theory that it is the transitory nature of the entry event and the structures associated with it rather than the absence of appropriate structural determinants which accounts for the seeming lack of neutralizing epitopes within gp41. The applicants propose that these structural components, which form and function only during virus entry, and remain unexposed or are not present in the "native" fusion-inactive envelope complex, constitute a novel set of neutralizing epitopes within gp4l. The objectives of this research are the induction and characterization a humoral immune response targeting these "entry relevant" gp4l structures. It is hypothesized that immunization with constructs mimicking those highly conserved, gp41 structures involved in virus entry will elicit the production of broadly neutralizing antibodies targeting these structures.